J. Lipid Res.
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A more recent version of this article appeared on June 1, 2007

Papers In Press, published online ahead of print March 30, 2007
J. Lipid Res., doi:10.1194/jlr.M700047-JLR200
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Submitted on January 29, 2007
Revised on March 15, 2007
Accepted on March 29, 2007

Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue

Sandra C. Souza, Marcelo A. Christoffolete, Miriam O. Ribeiro, Hideaki Miyoshi, Katherine J. Strissel, Zlatina S. Stancheva, Nicole H. Rogers, Tara M. D'Eon, James W. Perfield, Hitomi Imachi, Martin S. Obin, Antonio C. Bianco, and Andrew S. Greenberg

Obesity and Metabolism Laboratory, JM-USDA HNRCA at Tufts University, Boston, MA 02111

Corresponding Author: andrew.greenberg{at}tufts.edu

In response to cold, norepinephrine (NE)-induced triacylglycerol hydrolysis (lipolysis) in adipocytes of brown adipose tissue (BAT) provides fatty acid substrates to mitochondria for heat generation (adaptive thermogenesis). NE-induced lipolysis is mediated by protein kinase A (PKA)-dependent phosphorylation of perilipin, a lipid droplet-associated protein that is the major regulator of lipolysis. We investigated the role of perilipin PKA phosphorylation in BAT norepinephrine-stimulated thermogenesis using a novel mouse model in which a mutant form of perilipin, lacking all six PKA phosphorylation sites, is expressed in adipocytes of perilipin knockout mice. Here, we show that despite a normal mitochondrial respiratory capacity, NE-induced lipolysis is abrogated in the interscapular BAT (IBAT) of these mice. This lipolytic constraint is accompanied by a dramatic blunting (~70%) of the in vivo thermal response to norepinephrine. Thus, in the presence of perilipin, PKA-mediated perilipin phosphorylation is essential for NE-dependent lipolysis and full adaptive thermogenesis in BAT. In IBAT of Peri KO mice, elevated basal lipolysis due to the absence of perilipin is sufficient to support a rapid NE-stimulated temperature increase (~3.0 C) comparable to wild-type mice. This observation suggests that one or more NE-dependent mechanisms downstream of perilipin phosphorylation are required to initiate and/or sustain the IBAT thermal response.


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